Marco Fogli1 Nicola Giordan2 Gianni Mazzoni1
1 Department of Biomedical Sciences, University of Ferrara, Ferrara, Italy
2 Clinical Research Department, Fidia Farmaceutici S.p.A., Abano Terme, Padua, Italy
Corresponding author: Nicola Giordan
Clinical Research Department, Fidia Farmaceutici S.p.A. Via Ponte della Fabbrica 3/A 35010 Abano Terme, PD, Italy Email: ngiordan@fidiapharma.it
Summary
Background: Tendinopathies are conditions char-acterized by activity-induced pain, local tender-ness and swelling for which a gold standard treat-ment is not established yet. Hyaluronic Acid (HA) is a key-molecule in several cellular activities and it is normally present in the extra-cellular matrix of tendons and ligaments. Amongst its proper-ties, HA injections may reduce pain and deter-mine disease-modifying effects. This study is an investigator-initiated open-label trial conducted to investigate the efficacy and safety of HA (500-730 kDa) peritendinous injections on pain reduction in patients affected by lateral elbow, Achilles or patellar tendinopathy.
Methods: A total of 71 tendons (34 with Achilles tendinopathy, 26 with lateral elbow tendinopathy, 11 with patellar tendinopathy) of 62 patients with painful tendinopathy were treated with a cycle of ultrasound-guided peritendinous injections one injection per week for three consecutive weeks. Efficacy assessments included changes in pain intensity measured by Visual Analogue Scale (VAS) at follow-up evaluations were performed 7 (V2), 14 (V3) and 56 days aften first treatment. An Ultrasound (US) assessment was also performed to evaluate changes in tendon thickness and neo-vascularization. Adverse events were recorded for safety analysis throughout the study. All re-sults were analyzed with descriptive statistics
ap-propriate to the nature of the variables.
Results: Significant reduction in VAS (p<0.001) from baseline was observed in Achilles (-6.16 ± 0.45 cm), patellar (-6.16 ± 0.72 cm) and lateral el-bow (-5.33 ± 0.43 cm) tendinopathies. The sagittal thickness decreased significantly from baseline at each endpoint (V3 day 14 and V4 day 56) in each type of tendinopathy analyzed (p<0.05). Neo-vascularization decreased for each tendons at V3 and V4, except for patellar tendon at V3 V1 (p=0.125). Nevertheless, reduction at V4 com-pared to baseline remained significant (p=0.016). Conclusions: US-guided HA (500-730 kDa) peri-tendinous injections determine significant pain relief and reduction in tendon thickness and neo-vascularization in US evaluations. The effect of HA did not show differences regarding the site of affected tendon. The treatment proved to be safe and very well tolerated.
Level of evidence: 4.
KEY WORDS: achilles, colour power doppler, hyaluronic acid, injection, patellar, tendinopathies, tennis elbow.
Introduction
Tendinopathies are multifactorial clinical conditions, which affect millions of people, producing disability that may last for several months1. Even mechanical overloading is considered as the main risk factor, oth-er intrinsic and extrinsic factors may contribute to the pathogenesis2, 3. In particular, poor vascularity, un-derload, age, gender, as well as genetic, endocrine and metabolic factors may play a central role4-6. Over the last decade, various models have been pro-posed to explain the intrinsic pathogenic mechanism of tendinopathies, which determine the failed healing response. Chronic stages of this condition are char-acterized by increased tenocyte apoptosis, disar-rangement of collagen fibres with decreased of type I collagen and altered type I collagen/type III collagen ratio and neoangiogenesis3.
Regardless of the cause or the type of tendon, clini-cal findings are quite uniform: patients refer pain at the affected tendon site, which sometimes arises dur-ing intense muscular effort or gradually if the effort is repeated and continuous; with time and continued ac-tivity, however, the pain may get worse and limit sport performance7.
Efficacy and safety of hyaluronic acid (500-730kDa)
Ultrasound-guided injections on painful
tendinopathies: a prospective, open label,
clinical study
In addition to pain, physical examination may reveal local tenderness, swelling and reduced articular range of motion8.
US is a valid tool to confirm the diagnosis, showing tendon thickening, focal hypo-echogenic areas with altered grey scale pattern and neovascularization de-tected at Power Doppler with sensitivity and specifity up to 90%9-12.
Although several options are available to manage tendinopathies, there is currently lack of consensus on the gold standard treatment. Eccentric exercise may be beneficial to ameliorate tendon structure13, while the role of oral and local NSAIDs is controver-sial in the short-term and could lead to several side effects in the long-term14.
Corticosteroid injections are widely used in clinical practice. Recent findings demonstrate that corticoid injection are worse than most conservative interven-tions in the long-term15they could weak tendon struc-ture enhancing the risk of tendon rupstruc-ture16. Several studies have shown that peritendinous application of hyaluronic acid (HA) is an effective therapeutic option for the treatment of chronic tendinopathy17, 18. Hyaluronic acid (HA) is one of the main components of synovial fluid, which is produced in the normal ten-don sheath and it is a main component of tenten-don ex-tracellular matrix19. In vitro models suggest that HA may increase tenocyte viability and collagen I produc-tion and deposiproduc-tion, with positive collagen I/collagen III ratio in a dose-dependent manner20. Its viscoelas-tic properties permit to reduce the surface friction of tendons increasing the gliding ability. It has been demonstrated that the application of HA, together with the formation of a network of the cells on the ten-don surface, results in the “gliding effect”21, 22. The aim of this prospective, open label, single-centre study was to evaluate the efficacy and safety of three US-guided peritendineous injections of 2 mL of medi-um weight HA (500-730 kDa) at an interval of one week on pain relief in patients affected by Achilles and patellar or lateral elbow tendinopathies.
Methods
Study designThis was an investigator-initiated, prospective, open-label, single-centre clinical study that evaluated the efficacy of HA US-guided peritendineous injections on pain reduction at rest and on movement in pa-tients with painful tendinopathies.
The study was approved by the local Ethical Commit-tee and was conducted ethically according to interna-tional standards23. Written informed consent was ob-tained from each patient before the inclusion.
Patients
All patients were enrolled over a 5-year period (2009 - 2013). Male or female patients aged ≥18 years in the symptomatic phase of chronic Achilles, patellar or lateral elbow tendinopathies (characterized by the
presence of at last one among: tendon swelling, pain on palpation, pressure and/or prehension, painful lim-ited range of motion) for ≥6 weeks and a pain score of at least 50 mm on VAS, confirmed by US evalua-tion, non-responders to conventional therapies for more than one month, were eligible.
Patients with recent tendon surgery, pregnant or breast-feeding and patients with diabetes (glycated haemoglobin > 6.7) were excluded from the study. Patients were also excluded if had been treated with systemic or topical steroids less than 1 month prior to inclusion or with NSAIDs therapies less than 10 days before inclusion. During the study, the use of any pain medication or physical therapy were not allowed. Demographic characteristics of patients and the pres-ence of concomitant hypothyroidism, diabetes and/or hypercholesterolemia were collected.
Study treatment
Sixty-two evaluable subjects were included (mean age 46.26) for a total of 71 treated tendons, classified as lateral elbow, Achilles or patellar tendinopathies. Patients received 3 ultrasound-guided injection of 2mL HA (500-730 kDa, Hyalgan®, Fidia Farmaceutici SpA, Abano Terme, Italy) once a week for 3 consecu-tive weeks.
Each injection was administered with a 25 Gauge needle approximately oriented 45° between the sagit-tal and coronal planes. Ultrasound imaging of treated tendons allowed examination of tendon morphology, detecting the areas of tendon degeneration and ten-don thickness. Neovascularization was assessed us-ing Power Doppler imagus-ing. The procedure was per-formed with a high-frequency (5-18 MHz) linear probe (MyLab25 Gold, Esaote SpA, Italy) and to be sure of the reproducibility of the assessment, the osteotendi-nous junction was chosen as a reference in probe po-sitioning.
Description of ultrasound guided injection scheme:
To treat patellar tendon, 2 mL of HA were injected distally the lower pole of the patella with the needle oriented in cranio-caudal direction at an angle of 45° to the Hoffa’s body.
For the Achilles tendon, 2 mL of HA were injected about 1 cm from the calcaneal insertion site and pro-ceeding proximally with the needle at an angle of 45° in the direction of Kager’s triangle.
For the epicondyle, 2 mL of HA were injected distal to the bone insertion site in the forearm direction, be-tween the extensor carpi radialis brevis and the finger extensor digitorum communis tendon.
Efficacy and Safety assessments
The primary endpoint was pain intensity changes from baseline (V1), assessed by VAS (0-10 cm) in which 0 represents ‘no pain’ and 10 represents ‘ex-treme pain’ at each study timepoint (V2 day 7, V3 day 14 and V4 day 56). Secondary variables were changes in tendon thickness measured by US and in
Power Doppler signal of the target tendon (severity was classified as: 0= “No vascularization”, 1= “Mild”, 2= “Moderate” and 3= “Severe”), according to Hok-srund et al.24at V3 and V4. Moreover, a clinical eval-uation of tendinopathy based on redness, warmth, swelling, tenderness, crepitus during movement and peritendinous effusion was performed at any study visit. Adverse events related and not related to the study drug were assessed for safety. Table I sum-marises demographic characteristics of sample. Statistical Analysis
Statistical analysis was performed using SAS®software release for Windows®(SAS Institute, Inc, Cary, North Carolina, USA). There was no control group and a sta-tistical calculation of sample size was not performed. The population size was enough to guarantee a 5% significance level. All statistical tests were 2-sided. To assess changes in pain and tendon characteristics at each endpoint, both the Student’s t test and the
Wilcoxon Signed Rank Test were used, considering
significant p-values ≤0.05. Finally, for each endpoint, an ANCOVA model was constructed to estimate the mean of the differences between the final and the ini-tial assessments, adjusting for the following indepen-dent variables present at baseline: sex, age, type of tendon treated, number of infiltrations performed and number of risk factors.
Safety population included all patients receiving at least 1 injection while Efficacy included all patients receiving at least 1 injection with at least 1 post-base-line value. Safety and Efficacy Populations were com-parable.
Results
Baseline characteristics
Sixty-two patients were included in the database, and 71 tendons were treated: 47.9% Achilles tendons (14 left and 20 right), 36.6% lateral epicondyles (6 left and 20 right) and 15.5% patellar tendons (4 left and 7
Figure 1. Subject disposition.
Table I. Demographic characteristics of sample.
Age N 62 Mean (SD) 46.26 (12.53) Median 46.00 (Min, Max) (16.71) Gender Male 47 (75.81%) Female 15 (24.19%)
right) (Fig. 1). Of the 62 patients included in the study, 47 were males (75.8%) and 15 females (24.2%). The mean age was 46.3 years (±12.5) (Tab. I).
The main risk factor present in the study population was hypercholesterolemia (16.1%) followed by hy-pothyroidism (9.7%). Diabetes was absent in 98.4% of the patients (Fig. 2).
Clinical outcomes
Pain decreased significantly from baseline at each endpoint (V2 day 17, V3 day 14 and V4 day 56) in each type of tendinopathy analysed (p<0.001) (Fig. 3). Specifically, in patients affected by Achilles tendinopathy, the mean VAS value was 7.92 cm (± 1.44) and it progressively decreased at V2 (7.59 cm ±0.97; p<0.001), V3 (3.91 cm±2.08; p<0.001) and V4 (2.02 cm±2.10; p<0.001). Similarly, in patients affect-ed by patellar tendinopathy the mean VAS value was (7.59 cm ± 0.97) and it progressively decreased at V2 (5.32 cm ±1.60; p<0.001), V3 (3.95 cm±1.64; p<0.001) and V4 (2.50 cm±2.16; p<0.001). In lateral elbow tendinopathy, the mean VAS value was 8.19
cm (± 0.79) and it progressively decreased at V2 (5.25 cm±1.80; p<0.001), V3 (3.39 cm±1.91; p<0.001) and V4 (1.74cm ±2.17; p<0.001)
Results from the ANCOVA model, after adjustment by sex, age, type of treated tendon, number of injections and number of risk factors, showed that the reduction in pain intensity was similar for each tendon and that there were no significant differences between types of treated tendon (p>0.05) (Tab. II).
Ultrasonographic examination
The sagittal thickness decreased significantly from baseline at each endpoint (V3 and V4) in each type of tendinopathy analysed (p<0.05). At baseline, mean sagittal thickness of Achilles tendon was 9.41mm (±2.38) at baseline, while it was 8.44 mm (±2.59) at V3 and 8.31 mm (±2.28) at V4. Mean sagittal thick-ness of patellar tendon was 7.09 mm at baseline (±1.65), while it was 6.55 mm (±1.36) at V3 and 6.16 mm (±1.58) at V4. For lateral elbow tendon, mean sagittal thickness was 6.20 mm (±0.78) at baseline, while it was 5.80 mm (±0.94) at V3 and 5.32 mm
(±0.87) at V4 (Fig. 4).
Regarding vascularity measured by Power Doppler, it was observed a significant decrease for each tendon at V3 and V4, except for patellar tendon from V3 to V1 (p=0.125). Nevertheless, reduction at V4 com-pared to baseline remained significant (p=0.016). (Fig. 5)
Safety
No serious adverse events were recorded. Two pa-tients reported transient adverse events during the study, one mild endometriosis and one mild episode of lumbosciatic syndrome, neither of them related to the study medication. The peritendinous injections of HA were well tolerated by all patients.
Discussion
Although tendinopathies are a common complaint, accounting for 30% of all musculoskeletal consulta-tions with a general practitioner, a gold standard treatment has not been identified yet25.
Hyaluronic acid has already been shown to be safe
and effective in treating osteoarthritis26, 27, while few studies have examined its effectiveness in tendon disorders.
The main objective of this study was to evaluate the efficacy and safety of HA injections of LMW-HA on pain reduction at rest and on movement in patients with painful tennis elbow, Achilles and patellar tendinopathies.
Kumai et al.28 found that a single injection of a high molecular weight (HMW) HA (2700 kDa), determined a prompt decrease in pain in 62 patients affected by Achilles, patellar and tennis elbow insertional tendinopathies in the short-term (1 week after injec-tion). Similarly, these study results indicate that symp-tom relief is achieved immediately after the first injec-tion. Furthermore, in our study, we observed that pain continue to decrease until the last follow-up (56 days). This may indicate that a cycle of 3 injections of 500-730 kDa HA may determine long-term decrease in pain in-tensity in patients affected by chronic tendinopathies non-responders to conventional therapies
In accordance with our findings, Frizziero et al.29, found that 3 injections of 500-730 kDa compared to low-ener-gy extracorpored shock-ware treatment (ESWT) pro-Figure 3. Mean pain intensity on VAS at each evaluation, by site of treated tendon. Legend: V1 Baseline; V2 Day 7; V3 Day 14; V4 Day 56.
Table II. Result from ANCOVA model in which the reduction in pain intensity was similar for each site and that there were no significant differences between types of treated tendon (p>0.05).
Mean (SD) Lower CL Upper CL
Type of treated tendon 95% 95% P-value
Achilles Tendon -6.16 (0.45) -7.05 -5.26 0.326
Lateral Epicondyle -5.33 (0.43) -6.20 -4.46 0.994
vide prompt clinical improvement that last until 3 months of follow-up in rotator cuff tendinopathy. Similar results were obtained also in mid-portion Achilles tendinopathy, in which 2 injections of a com-bination HA and mannitol were found to be superior to ESWT30. The Authors found 51.7% of participants in the HA group and 42.3% in the ESWT group were free of neovascularization within the tendon at Power Doppler US evaluation30. Our findings confirm the significant reduction in neovascularization detected at Power Doppler at V3 and V4 compared to baseline, except for V3 in patients treated for patellar tendinopathy, while reduction in V4 was significant.
Furthermore, it was observed a significant reduction in tendon thickness at V3 and V4 compared to the baseline that were similar and not dependent on the tendon.
The amelioration in US parameters could be partially explained by reduction in friction and peritendinous adhesions due to the lubrificant action of HA.These results may also indicate a possible “structure-modi-fying effect” here of HA (500-730kDa) on tendon, which need to be confirmed by further studies.The present study has the following 4 main limitations: the lack of a control group and randomization, the short-term follow-up and the lack of functional outcomes Figure 5. Mean vascularization on US at each evaluation by site of treated tendon. Legend: V1 Baseline; V3 Day 14; V4 Day 56.
Figure 4. Mean sagittal thickness on US at each evaluation by site of treated tendon. Legend: V1 Baseline; V3 Day 14; V4 Day 56.
specific for each tendon considered in this study. However, HA resulted efficient in short-term pain duction and safe, without relevant adverse effects re-lated to the molecule in the treatment of tendon pathology.
Conclusions
US-guided peritendinous injections of hyaluronic acid (500-730 kDa) in Achilles and patellar tendinopathy and lateral epicondylitis resulted in significant pain re-lief, decrease in tendon thickness and neovascular-ization without differences regarding the affected ten-don object of this study.
These clinical findings and the absence of adverse events, may confirm that hyaluronic acid represent a safe and effective option in the managements of painful tendinopathies.
Conflict of interest
This study was an investigator initiated study carried out in accordance with internationally recognized standards, such as the Declaration of Helsinki and the ICH’s Guideline for Good Clinical Practice. The Authors declare that they have no conflict of commer-cial interest. Nicola Giordan is an employee of Fidia Farmaceutici S.p.A. All Authors state, however, that Fidia Farmaceutici S.p.A. did not solicit this research project or protocols with investigators or institutions. Fidia Farmaceutici S.p.A. was not responsible for the initiation of the study and did not participate in the scientific design of the trial, in the creation of the pro-tocol, management of the study, data analysis, re-porting and in the decision to submit the manuscript for publication.
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